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1 Korean Journal of Obstetrics and Gynecology Vol. 53 No. 6 June 2010 골격이형성증의산전진단에있어서초음파및분자유전학적검사의유용성에관한고찰 이화여자대학교의학전문대학원산부인과학교실 1, 을지대학교의과대학산부인과학교실 2 김정명 1 김나연 1 김지윤 1 유시연 1 오관영 2 박원일 2 이경아 1 김영주 1 전선희 1 박미혜 1 Prenatal detection of skeletal dysplasia using ultrasound and molecular diagnosis Jung Myung Kim, M.D. 1, Na Yeon Kim, M.D. 1, Ji Yun Kim, M.D. 1, Si Yeon You, M.D. 1, Kwan Young Oh, M.D. 2, Won Il Park, M.D. 2, Kyung A Lee, M.D. 1, Young Ju Kim, M.D. 1, Sun Hee Chun, M.D. 1, Mi Hye Park, M.D. 1 1 Department of Obstetrics and Gynecology, Ewha Womans University School of Medicine, Seoul; 2 Department of Obstetrics and Gynecology, Eulji University College of Medicine, Daejeon, Korea Objective: To determine the accuracy and usefulness of prenatal ultrasonographic and molecular genetic diagnosis in detection of skeletal dysplasia. Methods: This study was based upon data of the 17 cases of skeletal dysplasia diagnosed by prenatal ultrasound and 7 cases by molecular diagnosis performed among the 17 cases and the 2 cases who has familial skeletal dysplasia by molecular diagnosis during the first trimester at Ewha and Eulji University from March 1998 to August A final diagnosis was sought on the basis of radiographic studies, molecular testing, or both. Results: The mean gestational age at diagnosis was 24.9 weeks (range, 17 to 35 weeks). Nine cases were diagnosed before 24 weeks. A final diagnosis was obtained in 16 cases (94.1%). There was 1 false-positive diagnosis. The antenatal diagnosis was correct in 14 cases (82.4%). The 8 cases were prenatally confirmed and 1 case was postpartum confirmed using molecular genetic testing and accurate antenatal diagnosis and prediction was done. We were able to rule out skeletal dysplasia through chorionic villus sampling during the first trimester in the 2 cases with the family history with skeletal dysplasia. Conclusion: Prenatal diagnosis of skeletal dysplasia can be a considerable diagnostic challenge. However, skeletal dysplasia is correctly diagnosed on the basis of prenatal meticulous ultrasound and antenatal prediction of lethality was highly accurate. Using prenatal molecular diagnosis, skeletal dysplasia can be diagnosed at first trimester of pregnancy and nonlethal skeletal dysplasia can be confirmed when prenatal ultrasound was nonspecific. Key Words: Skeletal dysplasia, Prenatal ultrasound, Prenatal molecular diagnosis 골격이형성증 (Skeletal dysplasia) 은다양한예후를가진골격성장질환군을말하며, 비정상적으로뼈가성장 접수일 : 채택일 : 교신저자 : 박미혜 ewhapmh@ewha.ac.kr 하고발달하여골격이비정상적인크기및모양을보이게되는데, 질환에따라다양한임상양상및예후를보이게된다. 1,2 지난 30년동안골격이형성증은임상적, 방사선적, 병리학적양상을기준으로분류해왔으며이러한분류기준에는현재 DNA 분석의발달로골격이형성증을야기하는

2 대한산부회지제 53 권제 6 호, 2010 Table 1. Genes that can be screened or diagnosed in uterus Disease Genes Multiple epiphyseal dysplasia, pseudoachondroplasia COMP, COL9A1, COL9A2, COL9A3, MATN3 Ellis-Van Creveld syndrome EVC Osteogenesis imperfecta types I-IV, Ehlers-Danlos syndrome COL1A1, COL1A2 Achondrogenesis II, hypochondrogenesis, Kniest dysplasia, spondyloepiphyseal dysplasia, COL2A1 spondyloepimetaphyseal dysplasia, Stickler dysplasia Thanatophoric dysplasia type 1 and 2, achondroplasia, hypochondroplasia, other FGFR3 FGFR3 disorders, SADDAN dysplasia Diastrophic dysplasia, achondrogenesis type 1B, atelosteogenesis type II, multiple epiphyseal DTDST (SLC26A2) dysplasia (recessive), other diastrophic dysplasia variant disorders Cleidocranial dysplasia RUNX2 For a more detailed list of biochemical and molecular tests available for the diagnosis of skeletal dysplasia, see the University of Washington-sponsored WorldWideWeb page GeneTests ( COL1A1: Collagen Type1 Alpah 1, COL1A2: collagen type 1 alpha 2, COL2A1: collagen type 2 alpha 1, COL9A1: collagen type IX alpha 1, COL9A2: collagen type IX alpha 2, COL9A3: collagen type IX alpha 3, COMP: cartilage oligomeric matrix protein gene, EVC: Ellis-van Creveld, DTDST (SLC26A2): diastrophic dysplasia sulfate transporter (solute carrier family 26[sulfate transporter] member 2), MATN3: matrilin 3, RUNX2: runt-related transcription factor 2, FGFR: fibroblast growth factor receptor, SADDAN: severe achondroplasia with developmental delay and acanthosis nigricans. 것으로알려진 gene locus 와돌연변이들도포함되어있다 년처음으로골격이형성증에대한국제적명명법 (international nomenclature for skeletal dysplasias) 이제시되었고임상적특징이나방사선적특징을기초로하여분류되었으며 1983 년, 1997 년, 2001 년수정되어현재 international nosology and classification of constitutional disorders of bones 를기준으로분류되고있다 년에합의된수정안의가장중요한변화는골격이형성증과비슷한임상적특징을보이는이골증 (dysostoses) 이포함된것이다. 산전에골격이형성증은초음파검사및유전학적검사에의존하여진단하고산후에확진을내리기위해방사선검사나병리검사, 염색체검사등을시행하는경우가대부분이다. 골격이형성증중에서예후가치명적인경우보호자와상의하여향후임신유지여부를결정하는것이원칙이므로산전의명확한진단이매우중요하다. 예후가치명적이지않은 (nonlethal) 질환에이환된대부분의태아의경우, 임신중반기말이후부터골격길이의성장이둔화되어산전초음파검사의발달에도불구하고초기초음파검사만으로골격이형성증의진단및감별진단이어려운경우가있는데이러한경우에분자유전학 적진단은임상적으로매우중요하다. 최근 DNA 분석으로골격이형성증을일으키는 gene locus 와돌연변이들이확인되고있다 (Table 1). 5 따라서본연구를통해, 골격이형성증의산전진단에있어서초음파검사의정확성및분자유전학적검사의유용성을평가해보고자한다. 6,7 연구대상및방법 1998 년 3월부터 2005 년 8월까지이대목동병원과을지대학병원에서산전에초음파검사로골격이형성증이진단되었던 17예와그중에서골격이형성증의진단을위하여분자유전학적검사를실시하였던 7예와골격이형성증의가족력이있는가계에서임신제1 삼분기때분자유전학적검사를실시하였던 2예를대상으로하였다. 초음파검사에서짧은사지, 굴지증 (camptomelia), 흉곽형성부전증 (hypoplastic thorax), 골절 (fractures), 비정상적인뼈음영, 척추후만증 (kyphosis) 등의골격이상을보일때골격이형성증을의심하였다 (Table 2). 연골무형성증 (achodroplasia) 은산전초음파상두드러진이마, 낮은콧등 (nasal bridge), 넓은아래턱뼈를동반

김정명외 9 인. 골격이형성증의산전진단에있어서초음파및분자유전학적검사의유용성에관한고찰 한큰머리, Rhizomelic 형짧은사지, 경하게휜사지, 세번째손가락과네번째손가락사이가벌어진삼지창손 (trident hand) 등을보일때진단하였다.

불완전골형성증 (Osteogenesis imperfecta) 은심한소지증, 다발성골절, 뼈의저무기질침착등을보일때진단하였다.

굴지골격이형성증 (Camptomelic dysplasia) 은하지의장골이휘어있으면서소지증 (micromelia) 을보여어깨뼈의형성부전증등을보여진단할수있었다.

$of cases Skeletal anomalies short limbs 14 micromelia 7 mesomelia 6 camptomelia 1 hypoplastic thorax (CC/TC>60%) 9 fracures 1 abnormal bone density 1 kyphosis 1 syndactyly 1 Non skeletal anomalies$ facial dysmorphism 5 intestinal obstruction 1 CC: cardiac circumference, TC: thoracic circumference. 한사지의위치, 전반슬 (genu recurvatum), 곤봉발등을동반할때선천다발성관절만곡증 (arthrogryposis multiplex congenita) 을진단하였다.

facial dysmorphism 5 intestinal obstruction 1 CC: cardiac circumference, TC: thoracic circumference. 한사지의위치, 전반슬 (genu recurvatum), 곤봉발등을동반할때선천다발성관절만곡증 (arthrogryposis multiplex congenita) 을진단하였다.

3 김정명외 9 인. 골격이형성증의산전진단에있어서초음파및분자유전학적검사의유용성에관한고찰 한큰머리, Rhizomelic 형짧은사지, 경하게휜사지, 세번째손가락과네번째손가락사이가벌어진삼지창손 (trident hand) 등을보일때진단하였다. 치사성골격이형성증 (Thanotophoric dysplasia) 은넙다리뼈 (femur) 와위팔뼈 (humerus) 의길이가임신주수에비해 5% 이하로사지길이가짧으며종모양의좁은흉곽및두드러진이마와튀어나온눈, 편평한척추체, 전화기모양처럼굽은사지 (telephone receiver), 네잎클로버잎형두개골모양 (cloverleaf skull) 등을보일때진단하였다. 불완전골형성증 (Osteogenesis imperfecta) 은심한소지증, 다발성골절, 뼈의저무기질침착등을보일때진단하였다. 에퍼트증후군 (Apert syndrome) 은두개골조기융합증 (craniosynostosis), 단두증 (brachycephaly), 첨두증 (acrocephaly), 양안과다격리증 (hypertelorism), 높은이마, 납작한뒤통수, 납작한안면, 두번째, 세번째네번째손가락이붙은합지증인벙어리장갑모양손 (mitten hand) 등을보일때진단하였다. 굴지골격이형성증 (Camptomelic dysplasia) 은하지의장골이휘어있으면서소지증 (micromelia) 을보여어깨뼈의형성부전증등을보여진단할수있었다. 장골은정상소견을보이면서특징적으로짧고좁은흉곽을보이고갈비뼈의결손과척추의해체 (disorganization) 소견을보여자코-레빈증후군 (Jarcho-Levin syndrome) 을진단하였으며실시초음파검사상 (real-time sonography) 태아의움직임이거의보이지않으면서양수과다증, 이상 Table 2. Sonographic abnormalities Abnormalities No. of cases Skeletal anomalies short limbs 14 micromelia 7 mesomelia 6 camptomelia 1 hypoplastic thorax (CC/TC>60%) 9 fracures 1 abnormal bone density 1 kyphosis 1 syndactyly 1 Non skeletal anomalies facial dysmorphism 5 intestinal obstruction 1 CC: cardiac circumference, TC: thoracic circumference. 한사지의위치, 전반슬 (genu recurvatum), 곤봉발등을동반할때선천다발성관절만곡증 (arthrogryposis multiplex congenita) 을진단하였다. 초음파소견에서중증소지증 (severe micromelia), 흉곽형성부전증 (hypoplastic thorax), 골절등을보였을때예후가치명적일것으로판단하였으며이러한질환에는치사성골격이형성증, 불완전골형성증 II 형, 굴지골격이형성증, rhizomelic 형점성연골이형성증, 편평추치사성연골이형성증 (platyspondylic lethal chondrodysplasias), 단늑골다지증증후군 (short rib polydactyly syndromes) 등이있다. 8 골격이형성증의최종진단은출생후방사선과적검사 A B C D E Fig. 1. Infantograms of skeletal dysplasia. (A) Jarco-Levin syndrome. There are kyphoscoliosis and dyssegmentation of thoracic spines, agenesis of right upper ribs and fan-like appearance of right lower ribs. (B) Camptomelic dysplasia. There are bowing of both femur and hypoplastic scapula. (C) Achondroplasia. The long bones are rhizomelic shortening and mild bowing. Head is enlarged. (D) Osteogenesis imperfecta. There are severe micromelia, multiple fracture, brittle bone. (E) Thanatophoric dysplasia, type 1. Marked limb shortening and characteristic bowed telephone receiver femur are demonstrated

4 대한산부회지제 53 권제 6 호, 2010 Table 3. Prenatal diagnosis and final diagnosis for each case Case No. Prenatal diagnosis Gestational age at diagnosis (wk) Final diagnosis 1 Achondroplasia * 25 5 Achondroplasia 2 Achondroplasia * 24 Achondroplasia 3 Achondroplasia * 32 Achondroplasia 4 Achondroplasia * 35 Achondroplasia 5 Achondroplasia 29 Achondroplasia 6 Achondroplasia * 24 Nonspecific skeletal dysplasia 7 Thanatophoric dyplasia type I * 25 Thanatophoric dyplasia type I 8 Thanatophoric dyplasia type I 184 Thanatophoric dyplasia type I 9 Thanatophoric dyplasia type I 22 Thanatophoric dyplasia type I 10 Thanatophoric dyplasia type I 216 Thanatophoric dyplasia type I 11 Thanatophoric dyplasia type I 22 Thanatophoric dyplasia type I 12 Ostetogenesis imperfecta type II 17 Ostetogenesis imperfecta type II 13 Asphyxiating thoracic dysplasia 22 Ostetogenesis imperfecta type III 14 Ostetogenesis imperfecta type II 26 Campomelic dysplasia 15 Jarcho-Levin syndrome 312 Jarcho-Levin syndrome 16 Apert syndrome * 312 Apert syndrome 17 Arthrogryposis multiplex congenita 182 Arthrogryposis multiplex congenita * Molecular study case. 와분자유전학적검사로확진하였다 (Table 1). 결과골격이형성증이산전에초음파로진단된평균임신주수는 24.9 주였고 ( 범위 : 17~35 주 ), 이중 9예 (53%) 는 24 주전에진단되었다. 골격이형성증의최종진단은 16예 (94.1%) 에서얻어졌고, 1예의위양성진단이있었다. 최종진단결과산전진단은 14예 (82.4%) 에서정확하였다 (Table 3). 최종진단된골격이형성증의종류는연골무형성증 5 예, 치사성골격이형성증 5예, 불완전골형성증 2예, 굴지골격이형성증 1예, 자코- 레빈증후군 1예, 선천다발성관절만곡증 1예, 에퍼트증후군 1예였다. 골격이형성증의대표적인방사선사진 (infantogram) 과생후 1개월된에퍼트증후군의사진은그림과같다 (Figs. 1, 2). 이중 13예는보호자와상의하여임신중절을시행하였으며 4예는임신을유지시켰다. 임신중절을시행한골격이형성증 13예의평균진단임신주수는 22.7 주로임신을유지시킨 4예의평균진단임신주수 28주에비하여일찍진단되었다 (Table 4). 예후가치명적인골격이형성증은 9예로모두산전에치사성을진단하였다. 예후가치명적일것을의심할만한 Table 4. Outcome of pregnancy Final diagnosis No. of cases TOP Live birth Achondroplasia Thanatophoric dysplasia Osteogenesis imperfecta Camptomelic dysplasia Jarcho-levin syndrome Arthrogryposis multiplex congenita Apert syndrome TOP: termination of pregnancy. Fig. 2. Mitten hand of Apert syndrome in postnatal photograpy

Achondroplasia 2 None specific history Cordocentesis FGFR3:G380A Achondroplasia 3 Achondroplasia affected mother Cordocentesis FGFR3:G380A Achondroplasia 4 None specific history Cordocentesis

5 김정명외 9 인. 골격이형성증의산전진단에있어서초음파및분자유전학적검사의유용성에관한고찰 Table 5. Summary of molecular study in diagnosis of skeletal dysplasia Case Medical and family history Genetic method Mutation Diagnosis 1 Achondroplasia affected mother Cordocentesis FGFR3:G380A Achondroplasia 2 None specific history Cordocentesis FGFR3:G380A Achondroplasia 3 Achondroplasia affected mother Cordocentesis FGFR3:G380A Achondroplasia 4 None specific history Cordocentesis FGFR3:G380A Achondroplasia 6 None specific history Amniocentesis FGFR3:no mutation Nonspecific skeletal dysplasia 7 None specific history Postmortem blood FGFR3:G1108T Thanatophoric dysplasia type I 16 None specific history Amniocentesis FGFR2:S252W Apert syndrome 18 Osteogenesis imperfecta affected Chorionic villus sampling COL1A2:no mutation Normal baby mother (Col1A2:G982A) 19 Previous Osteogenesis imperfecta fetus delivery (Col1A1 985 insc) Chorionic villus sampling COL1A1:no mutation Normal baby FGFR: fibroblast growth factor receptor, COL1: type I collagen. 콜라겐 (type 1 collagen) 에돌연변이가없음을확인하여임신을유지하였으며건강한아이를분만하였다 (Fig. 3). A B 4예의연골무형성증과 1예의치사성골격이형성증에서는섬유아세포성장인자수용체 (fibroblast growth factor receptor) 3형의돌연변이를확인하였으며, 에퍼트증후군 1예에서는섬유아세포성장인자수용체 2형의돌연변이를확인함으로써진단을확진하였다. 산전초음파상연골무형성증위양성 1예에서임신종결후에확인한방사선검사상정상으로나왔고분자유전학적검사결과섬유아세포성장인자수용체 3형의돌연변이가발견되지않아연골무형성증이아님을확진할수있었다. Fig. 3. Molecular studies of the osteogenesis imperfecta mother and the normal fetus. (A) Osteogenesis imperfecta mother : Col 1A2:G982A heterozygote (red arrow), (B) Normal baby 고 찰 태아의골격은임신기간중임신제 1 삼분기때가장빠 초음파소견으로는중증소지증, 흉곽형성부전증, 골절등이있었다. 골격이형성증의진단및확진을위하여 9예에서분자유전학적검사를실시하였다 (Table 5). 불완전골형성증산모 1예및불완전골형성증의산과력이있었던산모 1예와산전초음파상연골무형성증이의심된 5예및치사성골격이형성증 1예, 에퍼트증후군 1예, 총 9예에서분자유전학적검사를실시하였다. 불완전골형성증산모 1예및불완전골형성증의산과력이있는산모 1예에서임신제1 삼분기때융모막융모생검술 (chorionic villus sampling) 을시행하여태아가제1형 르게발달하고성장하며, 임신 10주경이면어른과비슷한형태를보이기시작하여임신초기부터잘볼수있는구조이다. 9 선천성골격이형성증은사지, 흉부및두개골등의골격모양, 크기, 골밀도등에이상소견을보여다양한예후를가지는골격성장질환군을말하며 2 이질환의원인에관해서는많은학설이있다. 골격이형성증의산전진단은주로초음파검사를통해이루어지게되는데, 예후가치명적인골격이형성증의조기진단은조기에임신중절을가능하게하여임신후기에나타날수있는문제점들을예방할수있다는점에서중요하며따라서골격이형성증이산전에진단되면예후가치

6 대한산부회지제 53 권제 6 호, 2010 명적인질환과치명적이지않은질환의감별진단이매우중요해진다. 골격이형성증이의심되는태아의초음파를시행할때에는장골 (long bone), 흉부, 손, 발, 두개골, 척추, 골반등을포함해야한다. 5 장골을측정할때에는모든사지를포함해야하며각뼈의존재유무, 만곡 (curvature), 무기질화 (degree of mineralization), 골절등을평가해야한다. 흉부를평가할때에는심장의 4심방상 (four chamber view) 수준에서측정해야한다. 또한흉부의모양, 늑골의크기, 모양등도관찰되어야한다. 어깨뼈 (scapula) 가없는경우에는굴지골격이형성증을진단할수있다. 5,10 두개골은모양, 무기질화, 골화의정도등이평가되어야하며양안길이 (binocular diameter) 를측정하여두눈가까움증 (hypotelorism) 을배재해야한다. 척추는전체길이와측만증존재유무, 척추제의무기질화등을살펴보아야한다. 치사성골격이형성증의경우편평한척추체 (platyspondyly) 가전형적으로보이게된다. 골격이형성증을보이는상당수의태아는자궁속이나신생아시기에사망하거나선택적자궁종결술에의해분만된다. 사망한태아의기본검사에는외부모습을찍은사진, 사후전신방사선검사, 염색체분석을위한피부및다른조직의채취, 가능하다면추후생화학적, 유전학적연구가가능하도록섬유아세포의보존이포함된다. 5 이러한검사를시행하여얻어진정확한진단을바탕으로부모들에게추후임신에대한상담을시행해야한다. 정확한진단을바탕으로재발률을예상할수있으며추후임신을하였을때시행하게될산전검사와모니터링에대한계획을세울수있다. 5 선천성골격이형성증중에서가장많은빈도를차지하는질환중의하나가치사성골격이형성증이다. 9 임상적으로임신중기의대퇴골과상완골의길이가임신주수에비해 5% 이하로사지길이가짧다. 외관상의특징에의해 I형과 II형으로나눌수있는데 11 I형의경우 II형보다흔하며사지가전화기모양처럼굽은모양을보인다. II형의경우사지는곧은모양을보이며 I형보다는척추의편평도가덜하고네잎클로버잎형두개골모양을보인다. 두경우모두폐형성부전으로예후가치명적이어서대부분태아가자궁내에서사망하거나생후수주이내에사망하는것으로알려져있다 그이외에흉부의길이는정상이 지만종모양의좁은흉곽및두드러진이마와튀어나온눈, 편평한척추체등을보이게된다. 전체골격이형성증의초음파검사에의한진단은 94~96% 정도이나치사성골격이형성증의산전초음파검사에의한진단은 30~ 50% 정도라고보고되고있으며진단은보통임신 2,3 삼분기에할수있다. 15 치사성골격이형성증의원인에관한많은학설이있으나, 최근에는섬유아세포성장인자수용체 3형의돌연변이가원인중하나로인정되고있으며 16 일반적으로상염색체우성으로유전된다. 17 연골무형성증은짧은사지를보이는왜소증의가장흔한원인으로두드러진이마와낮은콧등을보이는소지증을보이는질환이다. 세번째손가락과네번째손가락사이가벌어진삼지창손을보일수있다. 상염색체우성으로유전되며 16.3 locus 에있는 4염색체의단완에위치하는섬유아세포성장인자수용체 3형의돌연변이에의해발생한다. 18,19 좁은척추관등의정형외과적문제를보이며정상지능을가지고사회에적응하며살아갈수있다. 불완전골형성증은골취약성을주요병변으로하는다양한증상의교원질질환군으로 7가지유형으로분류되는데, 이중 II형이치사성이다. 20 불완전골형성증의전형적인초음파소견은심한소지증, 다발성골절, 뼈의저무기질침착이다. 21 초음파를이용한조기진단은 1977 년 Mahoney와 Hobbins 22 에의해보고된이래많은보고가있었으며, 가장빠른초음파적진단은 15주에보고되었다. 26,27 17주이후에정상초음파소견이보인다면불완전골형성증 II형을배제할수있다. 28 대부분의불완전골형성증은프로콜라겐제1형 (type I procollagen) 의유전자인 COL1A1 (collagen type 1, alpha 1) 과 COL1A2 (collagen type 1, alpha 2) 의돌연변이에의해프로콜라겐제1 형생성에결손이생겨서발생한다. 20,29-31 대부분상염색체우성으로유전되며 III형만상염색체열성으로유전된다. 5,32 이를이용하여최근에는고위험임신에서융모섬유모세포를배양하여콜라겐합성을분석하고, 프로콜라겐제1 형의유전자를분석하여직접적으로돌연변이부위를찾아내어산전진단에이용하고있다. 33 불완전골형성증의가정에서두번째태아에게나타나는재발률은 6% 정도로, 이는부모중한명에서발견되는배선섞임증 (germ line mosaicism) 의결과로나타나므로 34 불완전골형성증의태아를분만한무증상의부모들에게는재발방지를

7 김정명외 9 인. 골격이형성증의산전진단에있어서초음파및분자유전학적검사의유용성에관한고찰 위한적절한상담이이루어져야한다. 불완전골형성증 II형과같은치명적인형태에서는산전검사로조기에발견하여적어도 24주이전에임신종결여부를결정하여야할것이다. 35 에퍼트증후군은매우드문질환으로두개안면과사지의기형을보이는질환이며 50% 이상에서정신지체를보이고있다. 상염색체우성으로유전되며대부분산발적으로발생한다. 보통두개골조기융합증, 단두증, 첨두증, 양안과다격리증, 높은이마, 납작한뒤통수, 납작한안면을보인다. 두번째, 세번째, 네번째손가락이붙은합지증인벙어리장갑모양손을보이며뇌량무발생, 경한뇌실확장증, 경추 5~6 번의경추융합등을보인다. 중추신경계이상의정도에따라정신지체의정도가달라지며심장기형도동반할수있다. 섬유아세포성장인자수용체 2형의돌연변이와관련있으며 36,37 산발적으로발생한경우에는재발할가능성은거의없으며부모의한명이질환을가진경우에재발률은 50% 이다. 굴지골격이형성증은경골이나비골과같은주로하지의장골이비정상적인굴곡을보이는질환이다. 주로상염색체열성양상을보이나산발적인상염색체우성양상을보일수있다. 17q24 에위치한 Y염색체의성결정유전자의 SOX9 의돌연변이와관련을보인다. 임신말기까지유지되더라도태어난후대부분호흡기문제로사망한다. 자코-레빈증후군은갈비뼈와척추골의결함으로보여짧은목, 짧고좁은흉곽이특징적인질환이다. 반면에장골의길이는정상범위이다. 임신말기까지유지되더라도태어난후대부분호흡기문제로사망한다. 선천다발성관절만곡증은운동의제한과관절의강직을보이는질환이다. 양수과다증, 이상한사지의위치, 전반슬, 곤봉발등을같이보일때진단이쉬워지며동반된기형에따라예후가달라진다. 골격이형성증은상대적으로드문질환으로다양한임상양상을보이기때문에산전에정확한진단을내리기어려울수있다. 그러나세심하고정확하게시행된산전초음파검사는태아의골격이형성증을진단하는데매우우수한진단방법으로, 본연구에서는최종진단결과산전진단은 82.4% (14 예 ) 에서정확하였다. 특히중증소지증, 흉곽형성부전증, 골절등의소견을이용하여예후가치명적인골격이형성증을정확히진단할수있었으며본연구에서는총 9예모두산전에진단할수있었다. 산전초음파가골격이형성증을진단하는데가장중요한역할을담당하더라도분자유전학적검사등을통해정확한진단을내려야한다. 특히비치사성골격이형성증인경우산전초음파상비특이적인소견을보여진단하기어려울때가많아확진검사로이용할수있다. 본연구에서는골격이형성증의가족력이있는 2예에서임신제1삼분기때융모막융모생검술을시행하여골격이형성증을배제할수있었다. 예후가치명적인골격이형성증인경우분자유전학적검사를통하여산전초음파로진단이불가능한임신제1삼분기때빠르게골격이형성증을진단및배제할수있다. 예후가치명적인골격이형성증의조기진단은조기에임신중절을가능하게하여임신중기나후기에나타날수있는문제점, 위험한질식분만, 불필요한제왕절개술등을피할수있다. 1. Parilla BV, Leeth EA, Kambich MP, Chilis P, MacGregor SN. Antenatal detection of skeletal dysplasias. J Ultrasound Med 2003; 22: Rimon DL, Lachman RS. The chondrodysplsias. In: Rimoin DL, Connor JM, Pyeritz RE, Korf B, editors. Emery and Rimoin s principles and practice of medical genetics. New York: Churchill Livingstone; p Savarirayan R, Rimoin DL. The skeletal dysplasias. Best Pract Res Clin Endocrinol Metab 2002; 16: Hall CM. International nosology and classification of constitutional disorders of bone (2001). Am J Med Genet 2002; 113: 참고문헌 5. Dighe M, Fligner C, Cheng E, Warren B, Dubinsky T. Fetal skeletal dysplasia: an approach to diagnosis with illustrative cases. Radiographics 2008; 28: Orioli IM, Castilla EE, Barbosa-Neto JG. The birth prevalence rates for the skeletal dysplasias. J Med Genet 1986; 23: Kaufman RL, Rimoin DL, McAlister WH, Kissane JM. Thanatophoric dwarfism. Am J Dis Child 1970; 120: Spranger J, Maroteaux P. The lethal osteochondrodysplasias. Adv Hum Genet 1990; 19: 1-103, Romero R, Athanassiadis AP, Jeanty P. Fetal skeletal anomalies. Radiol Clin North Am 1990; 28: Mortier GR, Rimoin DL, Lachman RS. The scapula as a window to the diagnosis of skeletal dysplasias. Pediatr Radiol 1997; 27: Tretter AE, Saunders RC, Meyers CM, Dungan JS, Grumbach K, Sun CC, et al. Antenatal diagnosis of lethal skeletal dysplasias. Am J Med Genet 1998; 75: Lee JY, Park SW, Park JH, Baek MJ, Lee MG, Song SA, et al. A case of the type I thanatophoric dysplasia diagnosed in the 2nd trimester. Korean J Obstet Gynecol 2005; 48:

8 대한산부회지제 53 권제 6 호, Baker KM, Olson DS, Harding CO, Pauli RM. Long-term survival in typical thanatophoric dysplasia type 1. Am J Med Genet 1997; 70: Jones KL. Thanatophoric dysplasia. In: Jones KL, Smith DW. Smith s recognizable patterns of human malformation. 6th ed. Philadelphia: Elsevier Saunders; p Doray B, Favne R, Viville B, Langer B, Dreyfus M, Stoll C. A repot of the diagnosis and dysplasia. Presented at the 4th International Skeletal Dysplasia Meeting; 1999 Jul 29- Aug 1; Baden-Baden, Germany. 1999: p Cohen MM Jr. Short-limb skeletal dysplasias and craniosynostosis: what do they have in common? Pediatr Radiol 1997; 27: Martinez-Frias ML, Ramos-Arroyo MA, Salvador J. Thanatophoric dysplasia: an autosomal dominant condition? Am J Med Genet 1988; 31: Velinov M, Slaugenhaupt SA, Stoilov I, Scott CI Jr, Gusella JF, Tsipouras P. The gene for achondroplasia maps to the telomeric region of chromosome 4p. Nat Genet 1994; 6: Le Merrer M, Rousseau F, Legeai-Mallet L, Landais JC, Pelet A, Bonaventure J, et al. A gene for achondroplasia-hypochondroplasia maps to chromosome 4p. Nat Genet 1994; 6: Rauch F, Glorieux FH. Osteogenesis imperfecta. Lancet 2004; 363: Ruvolo KA, Filly RA, Callen PW. Evaluation of fetal femur length for prediction of gestational age in a racially mixed obstetric population. J Ultrasound Med 1987; 6: Mahoney MJ, Hobbins JC. Prenatal diagnosis of chondroectodermal dysplasia (Ellis-van Creveld syndrome) with fetoscopy and ultrasound. N Engl J Med 1977; 297: Merz E, Grussner A, Kern F. Mathematical modeling of fetal limb growth. J Clin Ultrasound 1989; 17: Shalev E, Feldman E, Weiner E, Zuckerman H. Assessment of gestational age by ultrasonic measurement of the femur length. Acta Obstet Gynecol Scand 1985; 64: Warda AH, Deter RL, Rossavik IK, Carpenter RJ, Hadlock FP. Fetal femur length: a critical reevaluation of the relationship to menstrual age. Obstet Gynecol 1985; 66: Brons JT, van der Harten HJ, Wladimiroff JW, van Geijn HP, Dijkstra PF, Exalto N, et al. Prenatal ultrasonographic diagnosis of osteogenesis imperfecta. Am J Obstet Gynecol 1988; 159: Stephens JD, Filly RA, Callen PW, Golbus MS. Prenatal diagnosis of osteogenesis imperfecta type II by real-time ultrasound. Hum Genet 1983; 64: Munoz C, Filly RA, Golbus MS. Osteogenesis imperfecta type II: prenatal sonographic diagnosis. Radiology 1990; 174: Wenstrup RJ, Cohn DH, Cohen T, Byers PH. Arginine for glycine substitution in the triple-helical domain of the products of one alpha 2(I) collagen allele (COL1A2) produces the osteogenesis imperfecta type IV phenotype. J Biol Chem 1988; 263: Barsh GS, Byers PH. Reduced secretion of structurally abnormal type I procollagen in a form of osteogenesis imperfecta. Proc Natl Acad Sci U S A 1981; 78: Byers PH, Tsipouras P, Bonadio JF, Starman BJ, Schwartz RC. Perinatal lethal osteogenesis imperfecta (OI type II): a biochemically heterogeneous disorder usually due to new mutations in the genes for type I collagen. Am J Hum Genet 1988; 42: Steiner RD, Pepin M, Byers PH. Studies of collagen synthesis and structure in the differentiation of child abuse from osteogenesis imperfecta. J Pediatr 1996; 128: Pepin M, Atkinson M, Starman BJ, Byers PH. Strategies and outcomes of prenatal diagnosis for osteogenesis imperfecta: a review of biochemical and molecular studies completed in 129 pregnancies. Prenat Diagn 1997; 17: Fauci A, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, et al. editors. Harrison's Principles of Internal Medicine. 14th ed. New York: McGraw-Hill; Seol HJ, Kim MJ, Kim MK, Park HJ, Shin JH, An HS, et al. A Case of osteogenesis imperfecta: diagnosis in uterus by ultrasonogram. Korean J Obstet Gynecol 2003; 46: Ferreira JC, Carter SM, Bernstein PS, Jabs EW, Glickstein JS, Marion RW, et al. Second-trimester molecular prenatal diagnosis of sporadic Apert syndrome following suspicious ultrasound findings. Ultrasound Obstet Gynecol 1999; 14: Park WJ, Theda C, Maestri NE, Meyers GA, Fryburg JS, Dufresne C, et al. Analysis of phenotypic features and FGFR2 mutations in Apert syndrome. Am J Hum Genet 1995; 57: = 국문초록 = 목적 : 골격이형성증의산전진단에있어서초음파검사의정확성및분자유전학적검사의유용성을평가해보고자한다. 연구방법 : 1998년 3월부터 2005년 8월까지이대목동병원및을지대학병원에서산전에초음파검사로골격이형성증이진단되었던 17예와그중에서골격이형성증의진단을위하여분자유전학적검사를실시하였던 7예와골격이형성증의가족력이있는가계에서임신제1삼분기때분자유전학적검사를실시하였던 2예를대상으로하였다. 골격이형성증의최종진단은출생후방사선과적검사와분자유전학적검사로확진하였다. 결과 : 골격이형성증이산전에초음파로진단된평균임신주수는 24.9주였고 ( 범위 : 17~35 주 ), 이중 9예 (53%) 는 24주전에진단되었다. 골격이형성증의최종진단은 16예 (94.1%) 에서얻어졌고, 1예의위양성진단이있었다. 최종진단결과산전진단은 14예 (82.4%) 에서정확하였다. 골격이형성증의진단을위하여 8예에서산전에, 1예에서산후에분자유전학적검사를실시하였으며이를통해골격이형성증의예측및확진을할수있었다. 산전초음파상이상소견을보이지않지만골격이형성증의가족력이있는 2예에서임신제1삼분기때융모막융모생검술을시행하여골격이형성증을배제할수있었다. 결론 : 산전초음파검사는태아의골격이형성증을진단하는데매우우수한진단방법이며특히예후가치명적인골격이형성증을정확히진단할수있었다. 또한분자유전학적검사가족력이있는가계에서산전초음파로진단이불가능한임신제1삼분기때빠르게골격이형성증을진단할수있으며비치사성골격이형성증인경우산전초음파상비특이적인소견을보여진단하기어려울때확진검사로이용할수있다. 중심단어 : 골격이형성증, 산전초음파진단, 산전분자유전학적진단

0태아 초음파 검사-한글(10월25일).PDF

0태아 초음파 검사-한글(10월25일).PDF (Dysostosismalformation of bones either singly or in combinations) (Osteochondrodystrophiesabnormalities of cartilage and bone) (Osteolysisdisorders associated with multifocal pathologic resorption of